PT  - JOURNAL ARTICLE
AU  - Luo, Gang
AU  - Lin, Jianrong
AU  - Fiske, William D.
AU  - Dai, Renke
AU  - Yang, Tian J.
AU  - Kim, Sean
AU  - Sinz, Michael
AU  - LeCluyse, Edward
AU  - Solon, Eric
AU  - Brennan, James M.
AU  - Benedek, Irma H.
AU  - Jolley, Summer
AU  - Gilbert, Darryl
AU  - Wang, Lifei
AU  - Lee, Frank W.
AU  - Gan, Liang-Shang
TI  - CONCURRENT INDUCTION AND MECHANISM-BASED INACTIVATION OF CYP3A4 BY AN
 <span class="sc">l</span>-VALINAMIDE DERIVATIVE
AID  - 10.1124/dmd.31.9.1170
DP  - 2003 Sep 01
TA  - Drug Metabolism and Disposition
PG  - 1170--1175
VI  - 31
IP  - 9
4099  - http://dmd.aspetjournals.org/content/31/9/1170.short
4100  - http://dmd.aspetjournals.org/content/31/9/1170.full
SO  - Drug Metab Dispos2003 Sep 01; 31
AB  - DPC 681 (N-[(3-fluorophenyl)methyl]glycyl-N-{3-[((3-aminophenyl) sulfonyl)-2-(aminophenyl)amino]-(1S,2S)-2-hydroxy-1-(phenyl-methyl)propyl}-3-methyl-l-valinamide) is a potent peptide-like human immunodeficiency virus protease inhibitor that was evaluated in phase I clinical trials. In primary cultures of hepatocytes, DPC 681 significantly induced the testosterone 6β-hydroxylase activity of rat CYP3A, but not human CYP3A4. Western blot analysis, however, demonstrated a 3-fold increase in expression of CYP3A4 protein by 20 μM DPC 681 in primary cultures of human hepatocytes. Subsequent studies showed that DPC 681 was a potent inhibitor of human CYP3A4 (IC50 = 0.039 μM) and rat CYP3A (IC50 = 1.62 μM). Moreover, DPC 681 was a mechanism-based inactivator of CYP3A4 with KI and kinact of 0.24 μM and 0.22 min-1, respectively. Thus, DPC 681 is both a potent inhibitor and a strong inducer of CYP3A4. Induction of CYP3A4 by DPC 681 was masked in vitro by autoinactivation, similar to the protease inhibitor ritonavir. In pharmacokinetic studies in healthy human volunteers and rats, DPC 681 was found to highly autoinduce its metabolism. Human volunteers dosed with DPC 681 at 600 mg twice daily for 14 days had a 75% decrease in the mean area under the concentration-time curve and a more than 3-fold increase in apparent clearance as compared with that on day 1. Because the primary route of DPC 681 clearance is via CYP3A metabolism, the increased clearance observed in clinical studies is due to induction of human CYP3A4 expression. The American Society for Pharmacology and Experimental Therapeutics